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Derek Lowe's commentary on drug discovery and the pharma industry. An editorially independent blog from the publishers of Science Translational Medicine. All content is Derek’s own, and he does not in any way speak for his employer.

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The 2012 Nobel In Chemistry. Yes, Chemistry.

A deserved Nobel? Absolutely. But the grousing has already started. The 2012 Nobel Prize for Chemistry has gone to Bob Lefkowitz (Duke) and Brian Kobilka (Stanford) for GPCRs, G-protein coupled receptors.Update: here’s an excellent overview of Kobilka’s career and research.
Everyone who’s done drug discovery knows what GPCRs are, and most of us have worked on molecules to target them at one point or another. At least a third of marketed drugs, after all, are GPCR ligands, so their importance is hard to overstate. That’s why I say that this Nobel is completely deserved (and has been anticipated for some time now). I’ve written about them numerous times here over the years, and I’m going to forgo the chance to explain them in detail again. For more information I can recommend the Nobel site’s popular background and their more detailed scientific background – they’ve already done the explanatory work.
I will say a bit about where GPCRs fit into the world of drug targets, though, since they’ve been so important to pharma R&D. Everyone had realized, for decades (more like centuries), that cells had to be able to send signal to each other somehow. But how was this done? No matter what, there had to be some sort of transducer mechanism, because any signal would arrive on the outside of the cell membrane and then (somehow) be carried across and set off activity inside the cell. As it became clear that small molecules (both the body’s own and artificial ones from outside) could have signaling effects, the idea of a “receptor” became inescapable. But it’s worth remembering that up until the mid-1970s you could find people – in print, no less – warning readers that the idea of a receptor as a distinct physical object was unproven and could be an unwarranted assumption. Everyone knew that molecular signals were being handled somehow, but it was very unclear what (or how many) pieces there were to the process. This year’s award recognizes the lifting of that fog.
It also recognizes something else very important, and here I want to rally my fellow chemists. As I mentioned above, the complaints are already starting that this is yet another chemistry prize that’s been given to the biologists. But this is looking at things the wrong way around. Biology isn’t invading chemistry – biology is turning into chemistry. Giving the prize this year to Lefkowitz and Kobilka takes us from the first cloning of a GPCR (biology, biology all the way) to a detailed understanding of their molecular structure (chemistry!) And that’s the story of molecular biology for you, right there. As it lives up to its name, its practitioners have had to start thinking of their tools and targets as real, distinct molecules. They have shapes, they have functional groups, they have stereochemistry and localized charges and conformations. They’re chemicals. That’s what kept occurring to me at the recent chemical biology conference I attended: anyone who’s serious about understanding this stuff has to understand it in terms of chemistry, not in terms of “this square interacts with this circle, which has an arrow to this box over here, which cycles to this oval over here with a name in the middle of it. . .” Those old schematics will only take you so far.
So, my fellow chemists, cheer the hell up already. Vast new territories are opening up to our expertise and our ways of looking at the world, and we’re going to be needed to understand what to do next. Too many people are making me think of those who objected to the Louisiana Purchase or the annexation of California, who wondered what we could possibly ever want with those trackless wastelands to the West and how they could ever be part of the country. Looking at molecular biology and sighing “But it’s not chemistry. . .” misses the point. I’ve had to come around to this view myself, but more and more I’m thinking it’s the right one.

53 comments on “The 2012 Nobel In Chemistry. Yes, Chemistry.”

Derek
You make a very good case for their work, which is undoubtedly of Nobel quality, being viewed as chemistry. I guess that you could also describe much of it as molecular pharmacology.
I remember being entranced the first top I saw Lefkowitz lecture. Since then our understanding of GPCRs and especially beta receptors has come on in leaps and bounds, much of it from their work. We even have crystal structures of these membrane proteins. This has led to a burgeoning effort to crystallize GPCRs and the results are providing considerable insights into their structure and function.
The Heptares CEO recently said that their first crystallized class B GPCR has provided considerable insight into the different chemical strategies required to target that group of GPCRs

True. It’s a nice surprise since I did expect a prize but not so soon. Also as far as the “not chemistry” grouse is concerned, think about the chemistry that GPCRs effect; phosphorylation and salt-bridge breakage among others. Plus, isn’t binding considered “chemistry”? Doesn’t binding happen all the time in chemistry? In addition crystallographers have been awarded chemistry Nobels since 1962. I have a post on this by the way.

Yes, as a synthetic chemist working in the CRO industry..cannot deny the influence of GPCR ligands in Pharma R&D. Well deserved award…chemists in academia need to appreciate this..In Industry..Biology and Chemistry overlap all the time..no one is going to award a Nobel for a natural product chemist..gone are the days.

Bravo Derek, nice post. I have found myself on the ‘biologists are taking our nobel prize’ bandwagon more than once, and your comments have brought me back to reality. Also, a story that supports Derek’s point:
When I was in graduate school I minored in biochemistry. During the enzymology class the biologists got really annoyed with the chemists because it wasn’t that hard for us. I remember a classmate (and girlfriend) once asked me how I got a specific question correct that was not explicitly covered beforehand. I told her that the cofactor (the structure was drawn out on the test) wanted to become aromatic, so it probably donated a hydride to whatever reaction it was a part of; I sort of figured it out from there. She looked at me like I had five heads.

Maybe the problem here is that these winners are not members of traditional chemistry departments. This trend raises the question as to the relevance of our academic discipline as stand alone entity. Perhaps the time has come to deconstruct chemistry departments and move chemistry staff into med-schools, pharmacology departments, agricultural science departments, vet schools, material science departments, engineering departments, etc.? It is we chemists who are needed in these departments as their worlds become ever more molecular. Is it the time for chemists to accept a greater calling in the new order of molecular science?

@ @#8 Anonymous: Sorry, but have to respectfully disagree. I am complete agreement with chemistry Nobels going to work with more of biological(or physics/materials) slant – much for similar that reasoning that Derek had eloquently stated. So I shall spare the details. However, traditional chemistry are to stay as is and must. It is the the fundamental understanding of chemical concepts and their application to other fields such as the ones you mentioned enables the evolution and success of such fields. Therefore, it is those who need chemists (as you say)and need to learn chemistry and must COME to the Chemistry Department to acquire knowledge.

@6 – exactly why I enjoyed chemistry a lot more than biology/biochem at the undergrad level, and why I stuck with it in grad school. Chemistry taught concepts, and biology-oriented classes were just memorization.
You have to know concepts in both areas to succeed at an advanced level, but that wasn’t clear to me as a college sophomore.

I do not know much about crystallography. Based on my understandings of other imaging methods I sometimes wonder whether crystallography is reproducible. Supposing one does crystallography on the crystals made either by Kobilka or himself, would he get the same structure? What about the structures used by the chemists to design drugs? Are these structures based on data from a single group? My assumption here is since it is quite difficult to do crystallography; there is little incentive to study the same protein once the structure has been published.

Very thought-provoking! After reading the 2011 Nature piece on Kobilka this morning, I noticed that none of the biology or chemistry faculty at Duluth scooped him up as an undergrad: they let him go off to med school. He could have had a PhD in chemistry, instead of a lowly MD! Kobilka moonlighted as an ER doc to support his research and family, then lost his HHMI funding. If NSF and the rest of the chemistry world had recognized and funded his work, then we could now feel proud of how we rewarded a brilliant scientist when the biologists and MDs had written him off. We had our chances to make Kobilka an academic chemist, and we lost them.

@12
X-Ray Crystallography is highly reproducible. There can be some variation in crystal structures, hence the necessity for crystallization under a variety of conditions.
It is of great interest to study crystal structures under every condition possible! Check out http://www.pdb.org for more information, here is a quick search on H. sapien hemoglobin:http://www.pdb.org/pdb/results/results.do?outformat=&qrid=9B643950&tabtoshow=Current
Hundreds of crystal structures have been shown.I personally use combinatorial methods for designing drugs based on computational analysis and published crystal structures, they are a vital tool for the modern biochemist.

Derek is absolutely correct, once again. Why is it called “molecular biology”? Because the molecules matter! End of story. The molecules are critical to how biology has gone from butterfly collecting and phenomenology to the molecular and information science that it is today.

There’s one person who can keep this all in perspective – the merits of chemists vs biologists (or physicists). Look (google) Richard Feynman I don’t like honors in YouTube and he will put you straight, even #7

It is worth noting that Nobel Prizes for membrane protein structures and mechanisms have often been through Chemistry. Starting with Peter Mitchell, the father of chemiosmotic theory, on to Harmut Michel, Huber and Diesenhofer for the photosynthetic reaction center, to Paul Boyer, John Walker and Jens Skou for their work on ion pumps and ATP synthase, more recently Rod McKinnon for the structure of the K channel, and now to Lefkowitz and Kobilka for GPCR. The study of pumps, channels, transporters and receptors falls in the intersection of chemistry, physics and biology.

Chemistry is the central science,that’s why.
Glad to see GPCRs getting its due, finally. I have been waiting for this since the late 90s. I wonder if crystallization of GPCRs is covered in
this Nobel citation.

Few of us probably understand the key developments that lead to the GPCR structures. Was it high throughput crystallization? Stabilizing detergents? Lipidic cubic phase? Expression technology (codon optimization etc.)? Beamline technology advances? Crystallography software?
All the above?
It is difficult to separate the real reasons from the the obligatory citations for justifying funding. It looks like the lysozyme fusion of the first structures wasn’t really key, since structures were obtained without it.

2 things: I have worked in drug discovery and while I cannot with certainty say I have never heard of this GPCR concept, I can at least say that I don’t remember ever having done so, and certainly wouldn’t have a clue what it stood for this morning.
B: If this is chemistry, which it might be, then I have to agree with #8,9 that the direction of the world’s chemistry departments is misguided (ok no surprise there…)

So out of curiosity, if the idea that chemistry is turning into biology is true, why are we not seeing more biology Nobel prizes awarded to biochemists? As an organic chemist, I feel like the field is becoming more and more marginalized even within chemistry. I’m not saying that the Nobel prize should go to an organic chemist (though the click reaction should be on the shortlist just because of how widely its used these days) but I would definitely like to see something with less of a life sciences bent to it. Yes, life sciences are important, but they’re not the end all be all of chemistry, and the contributions of chemistry are far broader than the collection of Nobel prizes in the last 5-10 years represents.

Can someone explain why Ray Stevens (Scripps) is not on the list… Ray’s work has led to a some very key contributions in the area of GPCR structure. Notable contributions over recent years include the following;
H1 Receptor – PDB 3RZE
S1P1 Receptor – PDB 3V2W
D3 Receptor – PDB 3PBL
CXCR4 Receptor – Multiple, including PDB 3ODU
A2A Receptor – Multiple, including 3EML
Can anyone furnish a plausible explaination?

@28: Here’s my guess: A purely structural prize would have gone to Kobilka, Stevens and Palczewski, leaving Lefkowitz out. The committee made a shrewd decision in splitting the prize, awarding one half to biochemical work (Lefkowitz) and the other half to structural work. For the structural work they picked only Kobilka, partly because his studies provided more insight into the actual workings of GPCR and partly because picking one and leaving out two would be less controversial than picking two and leaving out one.

@28 I too was a bit surprised Stevens was not included in the prize. Although the Kobilka GPCR complex structure is unique amongst its kind, the Stevens lab has contributed the most structural data by volume, by a wide margin. Going to see a talk by Cherezov (of LCP fame) tomorrow, I’m quite interested in what he’ll have to say on the news of today.
In general though found the tone of this post and most of the comments a bit silly, hoarding everything involving molecules somewhat strictly under The Chemistry Umbrella. While molecular biology and protein chemistry are part chemistry, they’re also part something else and it really shows. It’s all biochemistry: part chemistry and part biology with a healthy dose of physics. I’d be very careful in stating that the future of life sciences rests on the shoulders of the chemists of today.

@6: Likewise. While I was an organic grad student I took an elective enzyme structure & mechanism grad course in the Biochem Dept. The prof began by giving the class a diagnostic series of electron-pushing exercises–a straightforward breeze for me, but a lot of trouble for the biochemists.

@ 29 and 30 – Curious Wavefunction and Markusk:
Thank you for your posts. “Curious”, I do agree that the work of Kobilka has proven extremely insightful and the scenario you suggest certainly sounds plausible (though unfortunate).
However, along with “Markusk” I do feel that what the Stevens group has contributed, in not only volume but structural diversity (class A, class B, antagonists, agonists etc), should have been recognized. But as the French say, C’est la vie.
One further comment. Crystallization of GPCRs is not at all trivial by any means (hence the 2012 prize). Both Kobilka and Stevens (plus one or two others such as Tate) have made tremendous contributions toward the ultimate practical application of this in the drug discovery environment.
Now, is SBDD required for finding new medicines that modulate GPCR’s? Well clearly not – given that over the last 50 plus years new medicines targeting these receptors have been discovered (particularly against class A GPCRs). However, for class B or C GPCRs, it has been much more difficult – and this is where the pioneering work of Kobilka and Stevens et al will hopefully make a difference in the future!

@31 when did Stevens manage to crystallize class B GPCR?
As it’s seen from structures themselves, agonists and antagonists don’t really make tremendous conformational change in GPCRs without G-protein. So cocrystallization of complex was the major reason to pick Kobilka.
Also, among protein modellers there’s a belief that Stevens sometimes is messing up with crystallization water putting it where it “should” be regardless of actual electron density. Though Nobel committee hardly knew that :/
To sum up, I think that as long as there’s no single person (or three of them) who deserves a Nobel prize for developing structure-based drug design, the prize is given to ones who provide structures. The approach itself definitely deserves the prize, doesn’t it?

Great developments and a worthy of a Nobel, yes. However given a choice between a “Nobel Prize in Medicine or Physiology” and a “Nobel Prize in Chemistry” I would tend to put GPCRs into a physiology domain.

In terms of quantity, Stevens has certainly gone after (and solved) the bulk of GPCR structures to date, but all since 2006/7:http://gpcr.scripps.edu/
Curious is right on regarding the judicious recognition. I think this is a sign that structures alone are not automatic winners anymore. Kobilka has been at this since his postdoc and has clearly taken up the mantle from Lefkowitz. He has amassed a ton of great biochemical work to complement the structural data. It’s great to see mentor / protege recognized together when many times Nobel winners rarely work together, or even compete as adversaries.

@10, outside of academia, I don’t know too many people who survives on “pure” chemistry. I hold the view that my purpose is to make the safest and most effective drug (fancy rxn would be nice if publications is a possibility). As such, I submit to the fact that my world does not revolve around chemistry alone.

Derek. Thank you for the great post. I’m always amazed how you manage to get out so much information each day.
@29 -31 Curious Wavefunction , Markusk, Chemist for Life. Great analysis on the GPCR structural biology leaders.
Palczewski, Stevens, Tate all deserve massive recognition for their cracking GPCR structures.
Markusk noted that the “Kobilka GPCR complex structure is unique amongst its kind” . This is the key point. Moreover, each one of the Kobilka structures marched increasingly forward toward an understanding of the structural mechanics of signaling, backed by tremendously innovative biochemistry and molecular biology.
However,it would also seem that Palczewski’s original Bovine Rhodopsin structure should have been included as a third award which, like Kobilka’s efforts, also required a tremendous effort in biochemistry. Remember, the Rhodopsin had to be purified and crystallized from cow eyes in the dark etc.
I’d also like to make a shout out for several of my sbio colleagues. Peter Nollert who was, and still is, an innovator on the use of LCP for protein crystal growth. He’s one of many crystallographers, like Kuhn and Cherezov and many others that have worked to bring GPCRs to their knees.

a great post. I was definitely (probably still am) grousing. But even if biology is turning into chemistry, awarding the prize to work based so heavily on biology takes the award and recognition away from other fundamental discoveries in chemistry.
I agree with the post that chemistry is then just applied physics.. chemists should be winning the nobel in physics.

Sure, the GPCR research clearly deserves a Nobel.
But why does this *have* to be an “either/or” decision?
Why not split the prize in two (its been done before) and give half for some *real* chemistry 😉

I feel that some of us have heard the call, whilst others amongst us are still contemplating their role in this state changing approaches to science.
I tend to choose being called a scientist, rather than a (bio)chemist. So many things are just names. The traditionally different fields of biology, chemistry AND physics are finally merging into Molecular Science. This is indeed an epic event and seems well-reflected in the past years nobel prizes.
And we are still striving further to find the theory of everything. This is great. I am very proud to experience this time of change.

I noticed an interesting point in the Nobel citation. One key paper by the winners was the cloning paper for the B2-AR gene. Much of the work was done at a pharmaceutical company and the first and last authors worked at this company. How likely is something like this to occur today?
I was also initially surprised that Ray Stevens was not included, but the awardees have a long history of contributions beyond structural studies.

The case can be made that several things set Dr. Kobilka apart from the other (outstanding crystallographers) who have contributed to the GPCR field. (1) He was in on the original cloning of B2AR when he was a postdoc in Lefkowitz’s lab. (2) Long before the crystal structures he was making major contributions to our understanding of the multi-state nature of GPCRs. In my opinion he has been the pioneer developing the notion that GPCRs are not just two-state signaling proteins. (3) The structure of the active state receptor in complex with a G protein was sort of a “holy grail” and his lab is the one that determined it. If you go to the Nobel web site there is an excellent and meticulous description of who did what in the GPCR field, written by a Nobel committee member.